A hidden mark of a troubled past: neuroimaging and transcriptomic analyses reveal interactive effects of maternal immune activation and adolescent THC exposure in the absence of overt behavioural disruptions

Maternal exposure to infections during gestation has been shown to predispose individuals to develop schizophrenia. In addition, clinical data suggest that cannabis use could trigger disease onset in vulnerable individuals. However, the question of causality remains unclear. To shed light on this issue, we used a rat model of maternal immune activation combined with exposure to increasing doses of THC during adolescence in animals of both sexes. We studied several behaviours at adulthood that resemble specific symptoms of schizophrenia (working memory impairments, sensorimotor gating deficits, alterations in social behaviour, anhedonia, and potential alterations in implicit learning). In addition, we performed positron emission tomography on two time points to search for affected brain regions and then obtained brain samples of one of these affected regions (the orbitofrontal cortex) to carry out RNAseq analyses, which were also performed in peripheral blood mononuclear cells. Strikingly, while there were no overt behavioural disruptions, our PET scans revealed several brain alterations that relied on the combination of both hits. Maternal immune activation affected glutamatergic and serotoninergic genes, and the combination with THC shifted their expression from down-regulation to up-regulation. In the peripheral cells, interactive effects were observed on inflammatory pathways and some genes are proposed as biomarkers of the disease. These results suggest that the combination of these two vulnerability factors leaves a lingering mark on the body which could predispose to the disease, even before behavioural alterations manifest.已有研究表明，妊娠期母体感染暴露会增加个体罹患精神分裂症的风险。此外，临床数据显示，大麻使用可能触发易感个体的疾病发作。然而，二者间的因果关系仍未明确。为阐明这一问题，我们采用了母体免疫激活（Maternal Immune Activation）模型，结合青春期雌雄大鼠暴露于递增剂量的四氢大麻酚（Tetrahydrocannabinol, THC）的实验设计。我们检测了成年个体的多项行为，这些行为对应精神分裂症的特定症状：工作记忆损伤、感觉运动门控缺陷、社交行为改变、快感缺失以及内隐学习潜在异常。此外，我们在两个时间点进行正电子发射断层扫描（Positron Emission Tomography, PET）以筛选受影响的脑区，随后获取其中一个受累脑区——眶额叶皮层（Orbitofrontal Cortex）的脑组织样本进行RNA测序（RNAseq）分析，同时对外周血单个核细胞（Peripheral Blood Mononuclear Cells, PBMC）也开展了相同的测序分析。值得注意的是，尽管未观察到明显的行为异常，但PET扫描结果显示，仅当两种暴露因素联合作用时，才会出现多项脑结构与功能改变。母体免疫激活会影响谷氨酸能与5-羟色胺能基因的表达，而联合THC暴露则会将这些基因的表达趋势从下调转为上调。在外周血细胞中，我们观察到炎症通路存在交互效应，同时部分基因被鉴定为该疾病的潜在生物标志物。上述结果表明，这两种易感因素的联合作用会在机体内留下持久的印记，即使尚未出现行为异常，也可能增加个体罹患疾病的风险。